Hoffmann Olaf, Braun Johann S, Becker Doreen, Halle Annett, Freyer Dorette, Dagand Emilie, Lehnardt Seija, Weber Joerg R
Department of Neurology, Center for Anatomy, Charité-Universitätsmedizin Berlin, Germany.
J Immunol. 2007 May 15;178(10):6476-81. doi: 10.4049/jimmunol.178.10.6476.
Innate immunity relies on pattern recognition receptors to detect the presence of infectious pathogens. In the case of Gram-positive bacteria, binding of bacterial lipopeptides to TLR2 is currently regarded as an important mechanism. In the present study, we used the synthetic bacterial lipopeptide Pam3CysSK4, a selective TLR2 agonist, to induce meningeal inflammation in rodents. In a 6-h rat model, intrathecal application of Pam3CysSK4 caused influx of leukocytes into the cerebrospinal fluid (CSF) and induced a marked increase of regional cerebral blood flow and intracranial pressure. In wild-type mice, we observed CSF pleocytosis and an increased number of apoptotic neurons in the dentate gyrus 24 h after intrathecal challenge. Inflammation and associated neuronal loss were absent in TLR2 knockout mice. In purified neurons, cytotoxicity of Pam3CysSK4 itself was not observed. Exposure of microglia to Pam3CysSK4 induced neurotoxic properties in the supernatant of wild-type, but not TLR2-deficient microglia. We conclude that TLR2-mediated signaling is sufficient to induce the host-dependent key features of acute bacterial meningitis. Therefore, synthetic lipopeptides are a highly specific tool to study mechanisms of TLR2-driven neurodegeneration in vivo.
固有免疫依靠模式识别受体来检测感染性病原体的存在。就革兰氏阳性菌而言，细菌脂肽与Toll样受体2（TLR2）的结合目前被视为一种重要机制。在本研究中，我们使用合成细菌脂肽Pam3CysSK4（一种选择性TLR2激动剂）在啮齿动物中诱导脑膜炎症。在一个6小时的大鼠模型中，鞘内注射Pam3CysSK4导致白细胞流入脑脊液（CSF），并引起局部脑血流量和颅内压显著增加。在野生型小鼠中，鞘内注射激发24小时后，我们观察到脑脊液细胞增多以及齿状回中凋亡神经元数量增加。在TLR2基因敲除小鼠中未出现炎症和相关的神经元丢失。在纯化的神经元中，未观察到Pam3CysSK4本身具有细胞毒性。小胶质细胞暴露于Pam3CysSK4会在野生型小胶质细胞的上清液中诱导神经毒性特性，但在TLR2缺陷型小胶质细胞中则不会。我们得出结论，TLR2介导的信号传导足以诱导急性细菌性脑膜炎宿主依赖性的关键特征。因此，合成脂肽是研究体内TLR2驱动的神经退行性变机制的一种高度特异性工具。
